Erfan Bashar
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Spinal Muscular Atrophy

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Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.

Spinal muscular atrophy (SMA) is an autosomal recessive disease of the anterior horn cells and the most important treatable peripheral cause of the floppy infant. Loss of motor neurons produces a paralytic hypotonia: the infant is floppy and weak in matching proportion, with absent reflexes. Because treatment can only preserve neurons that are still alive, recognizing SMA early determines how much function the child keeps.

Genetics: SMN1 loss, SMN2 modification

Each person carries SMN1 on both copies of chromosome 5, producing full-length SMN protein needed for motor neuron survival. In about 95% of cases, SMA results from homozygous deletion of SMN1, and the motor neurons progressively degenerate.

A nearby backup gene, SMN2, differs by a single nucleotide in exon 7 that alters splicing, so only about 10–15% of its transcripts make functional protein. SMN2 copy number is the main severity modifier: SMA type 1 typically comes with 1–2 copies and type 4 with 3–5, but the correlation is imperfect and exceptions occur, so copy number guides expectations without fixing the prognosis alone.

Clinical picture

Weakness is symmetric and proximal, worse in the legs, with classic bedside signs: tongue fasciculations, absent deep tendon reflexes, frog-leg posture, severe head lag, and slipping through on vertical suspension. The face often stays expressive while the body is profoundly weak, and cognition and sensation are spared, so the infant looks alert. Respiratory failure drives mortality in severe disease: intercostal weakness with relative diaphragmatic sparing produces a bell-shaped chest and paradoxical breathing.

Functionally, severity runs from never sitting (type 1, historically fatal by age 2 without treatment) through sitting without walking (type 2) and walking with later loss (type 3) to adult onset (type 4). Modern usage increasingly describes non-sitters, sitters, and walkers, since treatment can move a child across the old boundaries.

The three disease-modifying therapies

All three raise functional SMN protein and all work best earliest, before motor neurons are lost.

  • Nusinersen, approved in 2016, is an antisense oligonucleotide that corrects SMN2 splicing toward exon 7 inclusion; because it does not cross the blood-brain barrier it is given intrathecally, starting with loading doses and continuing lifelong.
  • Risdiplam, approved in 2020, is a small molecule acting on the same splicing step and is taken orally.
  • Onasemnogene abeparvovec, approved in 2019, delivers a functional SMN1 copy with an AAV9 vector as a single intravenous infusion; it requires antibody screening with steroid cover and liver monitoring, since the vector can injure the liver.

Newborn screening by heel-prick blood spot now identifies affected infants before symptoms in many countries, which is exactly the window in which therapy preserves the most. Presymptomatic treatment trials have produced children developing normally at ages when untreated type 1 disease would have been fatal.

Supportive care

Disease-modifying drugs do not remove the need for multidisciplinary management: respiratory surveillance with non-invasive ventilation and cough assistance, nutritional and swallowing support, physiotherapy, orthopedic monitoring, and cardiac review. Responses to treatment have also revised an old assumption: motor units that appeared permanently lost can regain function when SMN protein returns early enough, so timing matters more than the static classification suggests.

Evidence anchors

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